The proposed work involves the development of new amino- protecting groups for use in the synthesis of sensitive, biologically active materials such as pharmaceuticals, peptides, proteins and polynucleotides. For ease of operation following the deblocking procedure, emphasis is placed on amino- protecting groups leading to (a) volatile, (b) totally insoluble or (c) infinitely water-soluble by-products. Emphasis is placed on groups deblocked by mild organic bases or under neutral conditions (solvent deblocking, hydrogenolytic deblocking). The former category includes members of the Fmoc and Imoc systems. The latter include the DBD-Tmoc and homobenzyloxycarbonyl systems. A whole new category of base- or nucleophile-sensitive protecting groups based on the Michael addition reaction will be examined. Such systems promise exceptional reactivity as well as selectivity via substituent control in both the substrate (nature of electron-withdrawing group, presence of beta-substituents) and the deblocking base (pKa, steric factors). A special concern covering all categories will be the design of groups capable of enhancing the solubility of medium- or long-chain peptides. The base-sensitive protecting groups will be used in further refinement of two new techniques for the rapid continuous synthesis of peptides: (a) the Fmoc/4-AMP solution synthesis and (b) the two-support inverse Merrifield synthesis. Other protecting groups will be tailored for peptide bond protection (solubility enhancement) or for specific application to the more difficult amino acids (Arg, His, Trp, Cys, etc.). The special application of the newer base-sensitive groups (descendents of the Fmoc function) to standard and continuous- flow Merrifield techniques will be studied. These newer groups are potentially capable of allowing for the fully automated, feedback-controlled synthesis of higher peptides.